DD261789A5 - PROCESS FOR PREPARING ANTIHYPERTONIC EFFECTIVE OCTAHYDRO-6-AZOINDOL DIPEPTIDE DERIVATIVES - Google Patents

Abstract

The invention relates to processes for the preparation of antihypertensive octahydro-6-azaindole dipeptide derivatives and pharmaceutical compositions of these derivatives of the formula I, wherein the substituents having the meaning given in the description which are prepared in which the protecting group R11 from a Compound of formula II, wherein the substituents having the meaning given in the description are removed, and if desired, the ester group R10 is removed by hydrolysis to form the compound of formula I in which R1 is H, and optionally a pharmaceutically acceptable salt of the product is formed. Formula I and II

Description

Field of application of the invention

This invention is concerned with methods of producing antihypertensive octahydro-α-azaindole dipeptide derivatives which possess inhibitory activity against the so-called "angiotensin converting enzyme" and are therefore of value in the treatment of certain circulatory diseases including hypertension and cardiac insufficiency. "

The enzyme renin is formed in the kidney, it causes the release of a decapeptide, angiotensin I via an OC-globulin. The "angiotensin converting enzyme" cleaves a terminal dipeptide unit from angiotensin I, whereby an octapeptide, angiotensin II, is formed , which is a potent hypertensive substance »In addition to a direct hypertensive effect, angiotensin II also stimulates the release of aldosterone, which also increases blood pressure by causing retention of sodium chloride and water.» Abnormal activation of the hormonal control system Renin angiotens are maintained is an important factor contributing to certain types of hypertonic diseases and congestive failure, and it is now certain that inhibition of the angiotensin converting enzyme is an effective step in the treatment of these conditions. "

2E9.87 "462907

Object of the invention

According to the present invention, compounds having inhibitory activity against the angiotensin converting enzyme of the formula

, -., CO ₀ HR ⁴ ' ²

CO-CH-NH-CH-CO ₀ R ¹

R ³ R ²

and pharmaceutically acceptable salts thereof and bioprecursers therefor, wherein:

R ^{1 is} H, C ₁ -C ₆ -alkyl, C ₁ -C ₄ -alkenyl or aryl- (C ₁ -C ₄ -alkyl)

R ^{2 is} C ₁ -C ₆ -alkyl, Cg-Cg-alkenyl, C -C -cycloalkyl or

substituted C -C -alkyl, wherein the substituent is halogen, hydroxy, C -C -alkoxy, aryl, aryloxy, aryl- (C -C -alkoxy), C ₃ -C -cycloalkyl, ^ iR ^ R, -NHCOR ^, -NHCO ₂ R ⁷ , guanidino, C ^ C ^ alkylthio, arylthio,) aryl- (C -C, -alkyl) thio or a heterocyclic

Group is, 3

R is C 1 -C ₆ alkyl, C 3 -C ₆ cycloalkyl or a substituted C 1 -C ₆ alkyl group wherein the substituent is -NHCOR ⁵ , -NHCO ₂ R ⁷ , -NR ⁵ R ⁶ , hydroxy, halogen, -CONR ⁵ R ^{6 is} C 1 -C ⁶ -cycloalkyl, guanidino, -CO ₂ H, -CO ₂ (C 1 -C 4 -alkyl), C 1 -C 4 -alkoxy, C 1 -C 3 -alkylthio, aryl or a heterocyclic group,

R -COR ⁵ , -CO ₂ R ⁷ , -SO ₂ R ⁷ , -SO ₂ NR ⁵ R ⁶ , -CONR ⁵ R ⁶ , -CON (R ⁵ ) -SO ₃ R ⁷ or -CON (R ⁵ ) COR ⁷ ,

wherein R and R are each independently of one another H, C 1 -C 4 -alkyl, C 3 -C -cycloalkyl, aryl, a heterocyclic radical or a substituted C 1 -C 4 -alkyl group,

wherein the group is substituted with one or more halogen atoms or a hydroxy, C "-C cycloalkyl, aryl, heterocyclic or

89 8 9

a -NR R group wherein R and R are each independently H ₁ C -C -alkyl, -CO (C -C -alkyl) or aryl, or

the two groups R and R, when attached to nitrogen, may be taken together to form a pyrrolidinyl, piperidino, morpholino, piperazinyl or N- (C ₁ -C ₄ alkyl) piperazinyl group, and

how R is defined is included.

R is defined as R, but hydrogen is not

In the above definition, the alkyl groups having three or more carbon atoms may be straight or branched chain unless otherwise specified. The term "aryl" as used herein means an aromatic hydrocarbon group such as phenyl or naphthyl optionally substituted with, for example, OH, CN-CF "C 1 -C 4 alkyl", C 1 -C 6 alkoxy; Halogen, fluoro, chloro, bromo or iodo, and the term "heterocyclic group" means a 5- or 6-membered, nitrogen, halogen, amino, or di (CC.-alkyl) amino group. Oxygen or sulfur-containing heterocyclic group which may be saturated or unsaturated and which may optionally contain one or two further nitrogen atoms in the ring and to which a benzo group is optionally fused or which may be substituted with, for example, halo, C -C -alkyl, hydroxy , carbamoyl oxo NH ₃ -. or mono- or di (C -C alkyl) amino groups may be subtituiert Specific examples include pyridyl, thienyl, furyl, indoyl, Benzthienyl-, imidazolyl, thiazolyl , Pyrrolidinyl, piperidino, morpholino and piperazinyl groups.

• i?

'Principle of the invention

J / The bicyclic system, to which reference is made herein as the 6-azaindole-octahydro can] be referred to alternatively pyridin systematically with octahydro-lH-pyrrolo 2,3-c £. The hydrogen atoms bonded to the carbon atoms linking the rings are preferably in the cis configuration. ·

The compounds of formula (I) contain several centers of asymmetry and therefore exist as enantiomers and diastereomers. The invention includes both the separated pure isomers and mixtures of isomers. Such compounds are preferred in which the 2-azaindole

2 carbon atom and the carbon atoms that the R - and

3 R- carry Sjibstituenten that have S configuration.

36.4

The pharmaceutically acceptable acid addition salts of the compounds of formula (I) are those synthesized from acids which form non-toxic acid addition salts, for example the hydrochloride, hydrobromide, sulfate or hydrogen sulfate, phosphate or acid phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate and tartrate salts. Salts may also be formed with bases, examples being the alkali metal salts, e.g. the sodium, potassium and calcium salts or salts with ammonia or amines, e.g. Dicyclohexylamine.

The term "bioprecursor" in the above definition means a pharmaceutically acceptable, biodegradable derivative of the compound of formula (I) which, when administered to an animal or human, in the body of the patient into a compound of the formula (I Such bioprecursors are well known to those skilled in the art and include, for example, biolabile esters such as the lower alkanoyloxymethyl esters, including their alkyl- and cycloalkyl-substituted derivatives. "For example, a specific example of 2-methyl-1-propionyloxy-1-propyl ester.

In a preferred group of compounds of formula (I), R is 2-phenethyl and R 1 is methyl or Ί-πιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιι R is preferably H or ethyl. Particularly preferred are compounds in which R is -CONR R, especially those wherein R is methyl and RH, or in which

4 7

R is SO R ', especially SO CH. £ 2 j

Particular particularly preferred compounds include: 1-Cn- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] -2-S-carboxy-6- (N-methylcarbamoyl) -octahydro-6-azaindole, 1- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanylJ-2-S-carboxy-6-methanesulfonyl-octahydro-6-azaindole and

- 6 - ^ asf

1- [Ν- (carboxy-3-phenylpropyl) -S-lysylJ-2-carboxy-6-methanesulfonyl-octahydro-6-azaindole.

The compounds of formula (I) are prepared by removing the carboxy-protecting group R from a compound having ν of the formula:

- (ID

IO

CO-CH-NH-CH-CO _n R

1 · l ·

wherein R ² and R ^{3 are} as defined above, R ¹⁰ corresponds to the above definition of R but excludes H, and R is a selectively removable carboxylic acid protecting group, and if desired by removal of the ester group R and optionally by formation a pharmaceutically acceptable salt of the product *

In this process, the carboxylic acid protecting group R can be any selectively removable ester group which can be removed under mild conditions without decomposing the final product of formula (I). In practice, a lower alkyl group such as methyl or ethyl is generally sufficient, since it can be easily removed by hydrolysis under mild conditions. If R is also e.g. is a lower alkyl group, it will of course also be hydrolyzed under these conditions to give the compound wherein R is H. Other possibilities for R are the benzyl group or the tertiary-butyl group. These can be removed by catalytic hydrogenation or by treatment with hydrogen chloride under anhydrous conditions. Under these

Conditions, the group R is not split off.

The starting substances of the formula (II) are prepared from a compound having the formula:

I 10

CO-CH-NH-CH-CO R

Wherein R, R, R and R are as defined above, prepared by:

a) Acylation with an acyl halide of the formula

R ⁷ COX

where X is a halogen atom, preferably bromine or chlorine,

) 1 < A

and R is as defined above, such being

Compounds of the formula (II) are obtained in which R

-COR and R is a radical other than hydrogen, or

Formylation with formic anhydride, where such

Compounds of formula (II) wherein R is -COH, or

b) Reaction with a halogenated formic acid ester of the formula

R ⁷ OCOX,

where R is as defined above and X is as defined above, such compounds having the formula

h 7 mel (II), in which R is -CO R, or

c) sulfonation with a sulfonic acid halide.enid or

Sulfamylation with a sulfaryl halide of the formula

R'S0 ₂ X or RR NSO ₃ X,

c C y

wherein R, R, R and X are as defined above to obtain those compounds of the formula (II) in which R. -SO R 'or -SO NR R is, or

d) reaction with an isocyanate of the formula

R ⁷ NCO, R ⁷ CONCO or R ⁷ SO ₂ NCO,

wherein R is as defined above, wherein such

4 Compounds of formula (II) wherein R is CONHR and R is other than hydrogen, or CONHCOR ⁷ or CONHSO R ⁷ , respectively, and wherein, when the product in which R is CONHR, by reaction with a connection with the formula

R ⁷ COX or R ⁷ SO ₂ X

wherein X is as defined above, acylate or sulfonate, such compounds of formula (II) arise in which R -CON (R ⁵ ) COR ⁷ and -CON (R ⁵ ) SO ₂ R ⁷ . is, or alternatively

Reacting the compound of formula (III) with phosgene and then with a compound of formula RR NH, wherein R and R are as defined above, to obtain those compounds of formula (II) wherein R is CONR ⁵ R ,

The conditions for the various stages (a) to (d) are generally conventional and the appropriate reagents, as well as the appropriate solvents and temperatures that can be used, and the time periods required for the reaction, by references to and Examples The various reagents required are all known compounds, either commercially available or preparable by literature methods. Substituents having reactive centers, eg, amino or carboxylic acid groups, must be protected during the reaction, and this can be achieved where needed by standard amino acid chemistry protecting group techniques. Such methods are well known to those skilled and are by John Wiley and Sons, New York, I96l, in standard works on the subject, for example, published in Green and Winitz "chemis _w try of the Amino Acids" - described.

The compounds of the formula (III) are obtained from the 6-azaindole (IV) as in the next reaction chain

2 3 10 11 prepared, wherein R, R, R and R are as above

12 and P and P are nitrogen protecting groups that can be selectively removed:

ei (ύ 7 ro

(IV)

(VII)

(VI)

(VIIIi

CH-NH-CH

R ° oco (ix)

(X)

(III)

The 6-azaindole (IV) is first reduced by catalytic hydrogenation to yield the tetrahydro-6-azaindole (V). This is sequentially protected at N-6 and N-I using conventional nitrogen protecting groups which are selectively removable. We have found that the choice of acetyl or trichloroethoxycarbonyl for N-6 and tertiary butyloxycarbonyl for N-I gives satisfactory results. The fully protected compound (VI) is then further reduced by catalytic hydrogenation to yield the octahydro-6-azaindole (VII). At this, the N-I position is selectively exposed by cleavage of the protective group. When P is tertiary butyloxycarbonyl, this can easily be achieved by treatment with anhydrous hydrogen chloride at 0 ° C. The product is then linked to the N-substituted amino acid fragment (IX) by means of a carbodiimide coupling reagent. In the event that the N-6 protecting group is trichloroethoxycarbonyl, removal thereof is achieved by treatment with zinc dust and acetic acid to form the intermediate compound (III). In a variant of this process, the compound of formula (VIII) is linked to a protected derivative of amic acid having the formula P 1 NHCH (ROCO H,

3 the protecting group P is split off and the product becomes

2 10 reacted with a compound of the formula CF SO OCH (R) CO_R to give the compound of formula (X).

In some cases, it is possible to choose a group for P that is needed for R. When acetyl is used in this manner, the compound of formula (X) functions directly as an intermediate of formula (II) wherein R is -COCH. is. Trichloroethoxycarbonyl, methanesulfonyl or N-methylcarbamoyl can be used in a similar manner in the intermediate compound of formula (X), which is then used directly in the deprotecting step.

Distance can be used, taking connections

k having the formula (I) wherein R is trichloroethoxycarbonyl, methanesulfonyl and N-methylcarbamoyl, respectively. The appropriate reaction conditions for all these stages as well as other variants and possibilities will be apparent to those skilled in the art.

As already mentioned, the compounds according to the invention are effective inhibitors of the angiotensin converting enzyme. Their activity against this enzyme is determined by using a modified method based on the method described by Cushman DW and HS Cheung, Biochemical Pharmacology, (I97l) i 20, l637i assay. The method involves the determination of the concentration of compound needed to reduce by 50 % the rate of release of radiolabelled hippuric acid from hippuryl-L-histidyl-L-leucine by rat kidney-isolated angiotensin converting enzyme.

Activity is measured in vivo following intravenous injection in anesthetized rats as described by I. L. Natoff et al., Journal of Pharmacological Methods, (19S1), 5, 305 and by DM Gross et al. , J. Pharmacol. Exp. Ther., (191l), 2l6 , 552. The inhibitor dose required to reduce the hypertensive response caused by intravenous injection of angiotensin I by 50 % is determined.

The anti-hypertensive activity of the compounds is evaluated by measuring the blood pressure drop following oral or intravenous administration to low-salt, diuresis-prepared, spontaneously hypertensive rats, or low-grade, kidney-induced hypertensive dogs.

For administration to humans in the treatment or prophylaxis of hypertension, the oral doses of the compounds for an average adult patient (70 kg) will generally be in the range of 2-100 mg per day. Thus, for a typical adult patient, individual tablets or capsules contain from 1 to 50 mg of active compound in a suitable pharmaceutically acceptable vehicle or excipient. The doses for intravenous administration are typically expected to be in the range of 10 -10 mg per single dose as needed. In practice, the physician will determine the appropriate dose most appropriate for an individual patient, and this will vary with the age, weight, and response of the individual patient. The above dosages are exemplary of the average case, but there may of course be single occasions where preference is given to higher or lower dose ranges, and such is within the scope of this invention.

For use in humans, the compounds of formula (I) may be administered alone, but generally they will be administered mixed with a pharmaceutical carrier selected for the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets with excipients such as starch or lactose or in capsules or ovules either alone or mixed with excipients or in the form of elixirs or suspensions with flavoring or coloring agents. They may be administered parenterally, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile solution which may contain other substances, e.g. enough salts or glucose to make the solution isotonic with blood.

- lh -

The compounds can be administered alone, but they can also be given together with other anti-hypertensive acting agents such as diuretics or Betabiockern, or optimize _t to the control of blood pressure with such other means as will prescribe the doctor or congestive To treat heart failure on any single patient in accordance with the established medical practice.

In a further aspect, therefore, the invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof or a bioprecursor therefor, together with a pharmaceutically acceptable diluent or carrier.

The invention also includes a compound of the formula (I) or a pharmaceutically acceptable salt thereof or a bioprecursor therefor for use in medicine, in particular in the treatment of hypertension or congestive heart failure in a human.

The invention also includes a method of treating hypertension or congestive heart failure which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a bioprecursor thereof or a pharmaceutical composition as defined above.

The preparation of the compounds of the invention and intermediates for use in their preparation is illustrated by the following examples.

J 6 J /

embodiments example 1

2-ethoxycarbonyl-1H-pyrrolo Γ2,3-c3pyridine

This substance (hereinafter referred to as 2-ethoxycarbonyl-6-azaindole) was prepared by the literature method of M.H. Fisher and A.R. Matzuk, J. Het. Chem. (1969), 6., 775.

Example 2

2-ethoxycarbony1-4,5,6,7-tetrahydro-6-azaindole and 2-ethoxycarbonyl-6-acetyl -k , 5,6,7 ~ tetrahydro-6-azaindole

A solution of 2-ethoxycarbonyl-6-azaindole (2h.5 g, 0.129 mol) in glacial acetic acid (1 L) was hydrogenated at 100 ° C and 100 psi (6.9 bar) over platinum oxide ( 3 g) for 2k hours. At this time, additional platinum oxide (4 g) was added and hydrogenation was continued for a total of 96 hours. The catalyst was filtered off and the solvent was evaporated in vacuo. The residue was dissolved in 200 ml of water and neutralized to pH 11 with 2M sodium hydroxide, and the precipitated solid (16.5 g) was collected by filtration. The filtrate was extracted with ethyl acetate to give further product (4 g). The combined solids were dissolved in methanol (50 ml), to which was added silica gel (k0 g), and the mixture was evaporated to dryness. Chromatography of the adsorbed substance over silica gel (300 g) with a chloroform / methanol solution (20: 1) eliminated traces of Ausgangsubtanz; Further washing with chloroform / methanol (10: 1) gave a minor impurity which, after trituration with diethyl ether, crystallized as a colorless crystalline solid (3.times.32 g, 10.9%), mp 106.degree.-108.degree. C., and which was obtained as 2-ethoxycarbonyl- 6

acetyl-4,5 ι 6,7-tetrahydro-6-azaindole was analyzed. Found: C 6l.00 H 6.98 N 11.98% Calculated: C 60.99 H 6.83 N 11.86% for ^C _l2 ^H i6 ^N 2 ° 3 A final washing with chloroform / methanol (5 J1), followed by evaporation of the eluent _/ afforded 2- Ethoxycarbonyl-4,516,7-tetrahydro-6-azaindole as a colorless crystalline solid (12.9 g, 51.6%), mp. 69 ° -169 x 5 ° C.

Found: C 61.71 H 7-34 N l4.4l '% Calculated: C 6l.84 H 7-26 N l4.42 % for ^c _l0 ^H ₁ i ₁ ^N ₂ ° 2

Example 3

2-ethoxycarbonyl-6- (2,2,2-trichloroethoxycarbonyl) 4 . 5,6,7-tetrahydro-6-azaindole

A solution of 2-ethoxycarbonyl-4,5 ₅ 6,7-tetrahydro-6-azaindole from Example 2 (8 g, Ö, 04L mol) in methylene chloride (200 ml) and triethylamine (4.15 g, 0.04l mol) was added to 0 C cooled and added dropwise within 30 min with a solution of chloroformic acid 2,2,2-trichloroethyl ester (8.69 g, 0.04 l mol) in 'methylene chloride (50 ml) and then stirred for 30 min at room temperature. The mixture was partitioned between water (50 mL), the organic phase separated, washed with water (50 mL), dried over sodium sulfate and evaporated to a yellow oil which was chromatographed on silica gel (150 g), eluting with chloroform and Chloroform / methanol (99: 1) and the expected pure product as a colorless solid (13.49 g, 89%), mp 126.5 ° -127 ° C (from ether / hexane).

Found: C 42.24 H 4.09 N 7.54 % Calculated: C 42.24 H 4.09 N 7.58 % for C "-H ₁ _Cl_N _o 0,

Be ispi el k

1- (tert-Butoxycarbonyl) -2-ethoxycarbonyl-6- (2,2,2-trichloroethoxycarbonyl) -4,5,6,7-tetrahydro-6-azaindole

A suspension of diethyl ether-washed sodium hydride (1.22 g, 0.0-1 mole) in dry dimethylformamide (50 ml) with a solution of 2-ethoxycarbony1-6- (2,2,2-trichloroethoxycarbonyl) was stirred under nitrogen at 0 ° C. -4,5,6,7-tetrahydro-6-azaindole from Example 3 (·3 · 4 g of O.O36 mol) in dry dimethylformamide (35 ml) was added dropwise within 30 min. Hydrogen evolution was observed and the mixture was stirred at room temperature for 10 minutes. The solution was cooled to 0 C and added dropwise with a solution of

Di-tert-butyl dicarbonate (8.94 g, 0.04 l mol) in dry dimethylformamide (25 ml) was added over 10 min. The mixture was allowed to stand at room temperature overnight, added water (100 ml) and the resulting solution was evaporated in vacuo to a low volume. The residue was diluted with water (200 ml) and extracted with ethyl acetate (4 × 100 ml), the combined extracts were washed with water (50 ml) and brine (3 × 100 ml), dried over sodium sulfate and turned into a brown viscous oil which was chromatographed on silica gel (250 g) eluting with hexane / methylene chloride (2: 1) followed by methylene chloride to give the title product as a pure, viscous oil (15 g, 8%).

Found: C 46.42, H 5.08 N 5-72 % Calculated: C 46.02, H 4.93 N 5 «96 % for C ₁ 8 ^H 23 ^C1 3 ^N 2 ° 6

Example S

1- (tert-butoxycarbonyl) -2-R, S -ethoxycarbonyl-6- (2,2,2-trichloroethoxycarbonyl) -octahydro-6-azaindole

A solution of 1- (tert-butoxycarbonyl) -2-ethoxycarbonyl-6- (2,2,2-trichloroethoxycarbonyl) -k , 5,6,7-tetrahydro-6-azaindole from Example k (15-3 g, 0.033 mol) in ethyl acetate (400 ml) was hydrogenated overnight via platinum oxide at 60 psi (~2 bar) and room temperature. The catalyst was filtered off * and the filtrate was concentrated in vacuo to a yellow oil which was chromatographed on silica gel (200 g) eluting with methylene chloride / hexane (9 ϊ 1) and then methylene chloride / methanol (99 ti) and the title product as a light yellow oil (13-29 g, 87 %)

Found: C ^ 6.19 H 5-86 N 6.08 % Calculated: C Ί5.63 H 5-75 N 5-91 % for C gH

gH

Example 6

2-R, S-ethoxycarbonyl-6- (2,2,2-trichloroethoxycarbonyl) -οctahydro-6-azaindole hydrochloride etherate

At 0 C, a suspension of 1- (tert-butoxycarbonyl) -2-R, S-ethoxycarbonyl-6- (2,2,2-trichloroethoxycarbonyl) octa-hydro-6-azaindole from Example 5 (ΐ3 × 24 g, 0.02 & mol) in dry diethyl ether (85Ο ml) with anhydrous hydrogen chloride gas and stirred at 0 C for k h. The resulting turbid solution was evaporated to dryness and the colorless solid obtained was triturated with dry diethyl ether to give the title product as a colorless solid (11-53 g, 95%) with no definable melting point.

Found: C 38.8o H 5.21 N 6.SS % Calculated: C 39-22 H 5-29 N 6.54 %

for C ₁₃ H ₁₉ Cl ₃ N ₂ O ^ χ x 1/4 HCl Et ₂ O

Example 7 '

1- (tert-butoxycarbonyl) -2-ethoxycarbonyl-6-acety1-4, 5, -6.7% trahydro-6-azaindole .

At 0 C, a suspension of diethylether-washed sodium hydride (0.28 g, 0.009 mol) in dry dimethylformamide (8 ml) with a solution of 2-ethoxycarbonyl-6-acetyl-4,5,7,7-tetrahydro-6-azaindole from Example 2 (2 g, 0.0005 mol) in dry dimethylformamide (2 ml) and stirred for 20 min. The mixture was allowed to come to room temperature and stirred for 1 h, during which time complete dissolution occurred. The solution was cooled to 0 ° C, over a period of 10 minutes, a solution of di-tert-butyl dicarbonate (1.85 g, 0.0005 mol) was added dropwise and the solution was stirred at room temperature for k h. The mixture was partitioned between water (200 ml) and extracted with ethyl acetate (4 × 100 ml), the organic extracts were washed with brine (3 × 100 ml), dried over sodium sulfate and evaporated to a yellow oil, which was purified over silica gel (20 g) was chromatographed eluting with methylene chloride / hexane (9: 1) to give the title product as a pale yellow oil (1.4 g, 49%). , * 'Found: C 60.12 H 7-32 N 8.15% Calculated C 6Ο.7Ο H 7-19 N 8.33 % for ". C -H ₂ ^ N ₃ O

.20- Uk "Γ"->

Example 8

1- (tert-butoxycarbonyl) -2-R, S-ethoxycarbonyl-6-acetyloctahydro-6-azaindole

A solution of 1- (tert-butoxycarbonyl) -2-ethoxycarbonyl-6-acetyl-4,5,6,7-tetrahydro-6-azaindole from Example 7 (1-3 g * 0.0039 mol) in ethyl acetate (120 ml). was hydrogenated over platinum oxide (130 mg) at 50 psi (3.5 bar) and room temperature for 18 h. Additional platinum oxide (130 mg) was added and hydrogenation was continued for k h at room temperature and 2 h at 50 ° C, whereupon the reduction was complete. The catalyst was filtered off and the filtrate was concentrated in vacuo to a light yellow oil which was chromatographed on silica gel (12 g) eluting with methylene chloride and then with methylene chloride / methanol (98: 2) to give the pure title product as a pale yellow oil ( 1.15 g, 86.5%)

Found: C 59-99 H 8.24 N 8.15 % Calculated: C 59-98 H 8.29 N 8.23 % for CH _ß N 0

Example 9

2-R, S-ethoxycarbonyl-6-acetyl-octahydro-6-azaindole hydrochloride etherate

A solution of 1- (tert-butoxycarbonyl) -2-R, S-ethoxycarbonyl-ö-acetyl-octahydro-ö-azaindole from Example 8 (11 g, Ο, 32 mol) in a mixture of diethyl ether (100 ml) and Ethyl acetate (20 ml) was treated at 0 C for a total of 30 minutes with anhydrous hydrogen chloride gas. The sols were removed in vacuo to give a gum which was triturated with diethyl ether and collected by filtration to give the title product as a colorless

hygroscopic solid (10 g, 100 %) without definable melting point, solvated with diethyl ether.

Found: C 49.54 H 7.89 N 8.94 % Calculated: C 49-83 H 8.20 N 8.94 % for

C ₁₂ H ₂₀ N ₂ O ₃ χ HCl χ H ₂ O x 1/4 Et ₂ O

Example 10 N- (l-S-ethoxycarbonyl-3-phenylpropyl) -S-alanine

This compound was prepared according to the literature procedure of H Urbach and R. Henning, Tetrahedron Letters, (1984), 25 , IIA3.

Example 11

! -CN- (1- S -ethoxycarbonyl-3-phenylpropyl) -S-alanyl-2-R, S-ethoxycarbonyl-6-acetyl-octahydro-6-azaindole

A stirred solution of N- (IS-ethoxycarbonyl-3-phenylpropyl) -S-alanine from Example 10 (0.97 g, 0.0035 mol), N-methylmorpholine (1.O6 g, 0.01 mol) and N-hydroxybenzotriazole (0.47 g, 0.0035 mol) in dry methylene chloride (100 ml) at 0 ° C with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (O.67 g, 0.0035 mol) and stirred at 0 ° C for 30 min. 2-R, S-ethoxycarbonyl-6-acetyl-octahydro-6-azaindole hydrochloride hydrate etherate (0.97 g, 0.0005 mol) was added and the solution was stirred at room temperature for 18 h. The reaction mixture was diluted with methylene chloride (100 ml), washed with sodium carbonate solution (10 % w / v, 3 × 50 ml), hydrochloric acid (IM, 3 × 50 ml) and brine (3 × 50 ml), dried over sodium sulfate and added to an oil in vacuo.

which was chromatographed on silica gel (12 g) eluting with methylene chloride / methanol (98.5: 1.5) to give the expected title product as a light yellow oil (O.38 g, 21.7 %) . ,

Found: C 64.11, H 8.09, · N 8.30 % Calculated: C 64.65, H 7-84, N 8.38 % for C ₂ HN Og

Example 12

! -CN- (1- S -carboxy-3-phenylpropyl) -S-alanyl3-2-R, S-carboxy-6-acetyl-octahydro-6-azaindole disodium salt hydrate

Sodium hydroxide solution (5M, 1 ml _i 0.005 mol) was added to a stirred solution of 1'-Fn- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] -2-R, S-ethoxycarbonyl-6-acetyl- octahydro-6-azaindole from Example 11 (0.33g, O.OOO66 mol) in tetrahydrofuran (20ml) and water (-15ml) and the solution was stirred at room temperature overnight. The reaction mixture was evaporated in vacuo and the resulting semi-solid material was dissolved in water (50 ml) and extracted with diethyl ether (3 x 20 ml). The aqueous phase was passed through a weakly acidic ion exchange resin (10 ml resin bed) to remove excess base, and the aqueous elution fractions were evaporated in vacuo to a semi-solid material, which was evaporated

from water (5 ml) to give the title product as its fluffy colorless disodium salt (0.17 g, 52.6 %)

Found: C 52 50 H 6.10 N 7 · 60 % Calculated: C 52.56 H 6-33 N 8.00 % for

^C 23 ^H 29 ^N 3 ° 6 ^Na 2 ^{x H} 2 °

Example 13

1-fN- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl J-2-R, S -ethoxycarbonyl-6- (2,2,2-trichloroethoxycarbonyl) -octahydro-6-azaindole .

A stirred solution of N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanine from Example 10 (3-91 g, O.Ol.mol) and N-hydroxybenzotriazole (I.89 g, 0.04 mol) in dry Methylene chloride (90 ml) at 0 ° C with ^ - (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (2.95 g, 0.015 mol) and stirred at 0 ° C for 5 min. 2-R ₁ S-ethoxycarbonyl-6- (2,2,2-trichloroethoxycarbonyl) -octahydr.o-6-azaindole hydrochloride etherate from Example 6 (6 g, 0.04 mol) and a solution of N-methylmorpholine ( 3 g, 0.03 mol) in dry methylene chloride (30 ml) was added, the temperature was allowed to rise from 0 C to room temperature over 3 h and then the reaction mixture was allowed to stand at room temperature for 72 h. The solution was washed with water (3 x 50 ml), sodium carbonate solution (10 % w / v, 2 x 50 ml), dilute hydrochloric acid (1M, 3 x 50 ml) and water (3 x 30 ml) and dried over sodium sulfate. The solvent was evaporated in vacuo to give a yellow oil which was chromatographed over silica gel (150g) with hexane / ethyl acetate (3il) as eluent to give the pure title compound as a pale yellow oil (4.48g, 50.4 %)

Found: C 53 · 50 H 6.37 N 6.36 % Calculated: C 52.96 H 6.03 N 6.62 % for C_ _Q H "oCl" N _o 0_

2o 30 3 3

Separation of the two diastereomers contained in this material was possible using silica gel column chromatography.

 j & 4 λ *

Example 14

1-Γν- (l-S-Carboxy-3-phenylpropyl) -S-alanyl] -2-R, S-carboxy-6- (2,2,2-trichloroethoxycarbonyl) -octahydro-6-azaindole disodium salt

A solution of 1- [_N- (1S-ethoxycarbonyl-3-phenylpropyl) -s-alanyl3-2R, S-ethoxycarbony1-6- (2,2,2-trx-chloroethoxycarbonyl) -octahydro-6-azaindole of Example 13 (0.23 gi Ο.ΟΟΟ36 mol) in tetrahydrofuran (20 ml) and water (15 ml) was added at room temperature with sodium hydroxide solution (5M, 0.6 ml, 0.003 mol) and stirred overnight at room temperature. The solvents were evaporated in vacuo, the resulting semi-solid material dissolved in water (50 ml), extracted with diethyl ether (3 x 20 ml), and the aqueous fraction was passed through a weakly acidic ion exchange resin (15 ml resin bed). to remove excess base. The product-containing fractions were combined and lyophilized from water to give the title product as its disodium salt (0.095 g, 42.4 %) m.p. 17O ° -173 ° C (dec.)

Found: C 46.96 H 5 · 17 N 6.75 % Calculated: C 42.28 H 4.53 N 6.75 % for

^C 24 ^H 28 ^C1 3 ^N 3 ° 7 ^Na 2

Example 15

1-ΓΝ- (1-S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] -2-R, S-ethoxycarbonyl-octahydro-6-azaindole

A solution of 1- ^ N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] -2-R, S -ethoxycarbonyl-6- (2,2,2-trichloroethoxycarbonyl) -octahydro-6-azaindole of Example 13 (4.16 g, Ο.66 mol) in glacial acetic acid (100 ml) was treated with freshly activated zinc dust (4 g, 0.06 mol) and overnight

stirred at room temperature. The mixture was diluted with water (100 ml), the excess zinc filtered off and the solid was washed well with chloroform (200 ml). The filtrate was evaporated to dryness, the resulting gum was taken up in water, the solution basified to pH 11 (5M NaOH), diluted with brine (100 ml) and extracted with chloroform (3 x 100 ml). The organic phase was separated, washed with water (100 ml), dried over sodium sulfate and evaporated to give the pure title product as a viscous foam (2.97 g »99%).

Example 16

1- [N- (l-S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] -2-R, S-ethoxycarbonyl-6-benzoyl-octahydro-6-azaindole

A solution of 1-fN- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl) 3-2-R, S -ethoxycarbonyl-octahydro-6-azaindole from Example 15 (0.98 g, 0.00108 mol) To a dry methylene chloride (15 ml) was added a solution of N-methylmorpholine (1.09 g, 0.00109 mol) in methylene chloride (5 ml), the solution was cooled to 0 C, with benzoyl chloride (0.152 g, 0.0001 mol) in methylene chloride (5 ml) and stirred overnight at room temperature. The solvents were removed in vacuo and the residue partitioned between ethyl acetate (50 ml) and water (20 ml). The organic phase was separated, washed with water (2 × 20 ml) and dried over sodium sulfate, and the solvent was removed in vacuo to give a yellow oil which was purified over silica gel (7 g) with ethyl acetate / hexane (1:10) and then Ethyl acetate / hexane (1: 1) as eluent to give the title product as a light yellow oil (O.kk g, 72 %) .

Example 17

1-CN- (IS-carboxy-3-phenylpropyl) -S-alanyl] -2-R ₁ S-carboxy-6-benzoyl-octahydro-6-azaindole hydrate

A solution of 1-N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanylH-2-R, S-ethoxycarbonyl-o-benzoyl-octahydro-oazaindole from Example 16 (0.42 g, O.OOO.74 raol). in tetrahydrofuran (10 ml) and water (10 ml) was added sodium hydroxide solution (5M, 1.5 ml, 0.0075 mol) and stirred at room temperature overnight. The solvents were removed in vacuo, the semi-solid residue dissolved in water (50 ml) and extracted with ethyl acetate (10 ml) and the aqueous phase passed over a strongly acidic ion exchange resin (15 ml resin bed) and the column was washed with The product-rich fractions were combined, evaporated and lyophilized from water to give the pure title product as a colorless flocculent solid (0.190 g, 47.3 %) with a melting point of 167 ° -169 ° C. (m.p. Zers.) Received. Found: C 62.21 H 6.35 N 7-77 % Calculated: C 61.86 H 6.85 N 7-72 % for

C ^C 28 ^H 33 ^N 3 ° 6 ^{x 2 H} 2 °

Example 18

! -CN- (l-S-ethoxycarbonyl-3-phenylpropyl) -S-alanylJ-2-R, S-ethoxycarbonyl-6-hexanoyl-octahydro-6-azaindole

This compound was prepared by the method described in Example 16 by reacting with hexanoyl chloride and as a pure yellow oil (79 ⁰ A) . Found: C 66.6l H 8.49 N 7.18 % Calculated: C 66.76 H 8.49 N 7-53 % for CH ^ N ₃ O ₆

Example 19

! -EN- (l-S-Carboxy-3-phenylpropyl) -S-alanyl] -2-R, S-carboxy-6-hexanoy1-octahydro-6-azaindole hydrate

This compound was prepared from the product of Example 18 by hydrolysis _i as described in Example 17 and was obtained as a pure colorless solid (28.6 %) having a melting point of 166 -165 C (dec.). Found: C 62.66 H 7.64 N 8.13 % Calculated: C 62. kO H 7-95 H 8.05 % for CH ₃₉ N ₃ O ₆ χ

Example 20

1-ΓΝ- (l-S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] -2-R, S-ethoxycarbonyl-6- (N-benzyloxycarbonylglycyl) -octahydro-6-azaindole

This compound was prepared from the product of Example 15 by acylation according to the method of Example 16 using the symmetrical anhydride derivative of N-benzyloxycarbonyl-rglycine and obtained as a pure viscous oil (76 %)

Found: C 64.58 H 7 · 23 N 8.22 % " Calculated: C 64.60 H 7.12 N 8.61 % for C" _H, _r N, 0 _D

3 5 y D 4 0 =

Example 21

! -CN- (1- S -carboxy-3-phenylpropyl) -S-alanyl3-2-R, S-carboxy-6- (N-benzyloxycarbonylglycyl) -octahydro-6-azaindole hydrate

Hydrolysis of the product of Example 20 by the method

2M 7-83

of Example 17 provided the title product as a pure, colorless, crystalline solid (60 %), mp 158-162 ° C (dec.).

Found: C 59-19 H 6.63 N 9-28 % Calculated: C 59-03 H 6.71 N 8.88 % for

x 2 H ₀ O

Example 22

1- [N- (1- S -carboxy-3-phenylpropyl) -S-alanyl] -2-R, S-carboxy-6-glycyl-octahydro-o-azaindole hydrate

A solution of 1- [_N- (IS-carboxy-3-phenylpropyl) -S-alanyl-2-R, S-carboxy-6- (N-benzyloxycarbonylglycyl) -octahydro-6-azaindole hydrate from Example 21 (0.24 g, O.OOO38 mol) in ethanol (32 ml) and water (8 ml) was hydrogenated at 60 psi (hl bar) and room temperature over palladium-charcoal catalyst (5 %, 50 mg) for 3 h. The catalyst was filtered off, the filtrate was concentrated to a small volume, the water was removed by azeotropic distillation with chloroform and the resulting cream solid was triturated with chloroform / hexane (1: 1) and collected by filtration to give the title product as a cream Solid (0.152 g, 8k%) with a melting point of 172 C (dec.). Found: C 58.06 H 7.12 N 10.27 % Calculated: C 57-72 H 7-73 N 11.70 % for

° 23 ^Η 32 ^Ν Λ ^XH 2 °

Example 23

1-fN- (iS-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] -2-R, S -ethoxycarbonyl-6- (N-methylcarbamoyl) octahydrate-6- azaindole

Methyl isocyanate (0.062 g, 0.0012 mol) was added at 0 ° C with stirring to a solution of 1- [N- (1-S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] -2-R, S-ethoxycarbonyl-octahydro -6-azaindole from Example 15 (0.5 g, 0.001 mol) in methylene chloride (25 ml) and the solution was stirred at room temperature overnight. The solvent was evaporated in vacuo and the oily residue was chromatographed over silica gel (8 g) with methylene chloride and then with methylene chloride / methanol (98 × 5: Ι ×) as eluent to give the pure title product as a colorless oil (0.25 g, 49.7 %) .

Found: C 6l.l9 H 7.64 N 10.31 % Calculated: C 6l.22 H 7.63 N 10.50 %

^{for C} 2 ^H ₇ ^N 4 4o ° ^x 6 ° · ^{2 CH} 2 ^C1 2

Example 24

1-CN- (1-S-Carbo) y-3-phenylpropyl) -S-alanyiP-2-R, S-carboxy-6- (N-methylcarbamoyl) -octahydro-6-azaindole disodium salt hydrate

This compound was prepared from the product of Example 23 by hydrolysis by the method of Example 14 to give the pure title product as its disodium salt as a fluffy, colorless solid (0.159 g, 70 %) with a melting point of 17O ° -173 ° C (dec.). Found: C 50.78 H 6.13 N 9.82 % Calculated: C 50.27 H 6.42 NlO.20 %

for C ₂₃ H ₃₀ N ₄ O ₆ Na ₂ χ 2.5 H ₃ O

Example 2S

1-tert-Butoxycarbonyl-2-R, S-benzyloxycarbonyl-6- (2,2,2-trichloroethoxycarbonyl) -octahydro-6-azaindole

A solution of 1-tert-butoxycarbonyl-2-R, S-ethoxycarbonyl-6- (2,2,2-trichloroethoxycarbonyl) -octahydro-6-azaindole (4.2 g, 0.0088 mol) from Example 5 in benzyl alcohol (35 ml). Titanium tetraethylate (O.67 g, 0.0029 mol) was added under dry nitrogen and heated to 100 ° C. for 16 h. The cooled mixture was acidified with 1M hydrochloric acid and the benzyl alcohol was removed by distillation. The residue was dissolved in ethyl acetate (100 ml) and the solution washed with brine (50 ml), dried over sodium sulfate and evaporated to a yellow oil which was purified over silica gel (100 g) with methylene chloride and then with methylene chloride / methanol (99: 1). 1) was chromatographed as eluent to give the pure title product (2.02 g, 43%) as a pale yellow oil. Found: C 51-53 H 5.42 N 5.09 % Calculated: - C 51-55 H 5-37 N 5-23 % for

^C 23 ^H 29 ^C1 3 ^N 2 ° 6

Example 26

2-R, S-benzyloxycarbonyl-6- (2,2,2-trichloroethoxycarbonyl) -octahydro-o-azaindole hydrochloride

At 0 C, a solution of 1- tert -butoxycarbonyl-2-R, S-benzyloxycarbonyl-6- (2,2,2-trichloroethoxycarbonyl) -octahydro-azaindole (I.96 g, O.OO366 mol) from Example 25 was obtained in anhydrous diethyl ether (125 ml) with gaseous hydrogen chloride for 30 minutes. The solution was evaporated to dryness and the resulting sticky gum redissolved in ether (20 ml) and reintroduced.

evaporated to give a colorless solid which proved to be the pure title product (1.69 g, 98 %) .

Found: C 45-44 H 4.68 N 6.05 % Calculated: C 4 5-78 H 4.70 N 5-93 % for

^C l8 ^H 2i ^C1 3 ^N 2 ° 4 ^{x HC1}

Example 27

1-ΓΝ- (l-S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] -2-R, S-benzyloxycarbonyl-6- (2,2,2-trichloroethoxycarbonyl) -octahydro-6-azaindole

This compound was prepared using the general method of Example 11 by reaction of the N-hydroxysuccinimide ester of N- (IS-ethoxycarbonyl-3-phenylpropyl) -S-alanine with 2-R, S-benzyloxycarbonyl-6- (2.2 , 2-trichloroethoxycarbonyl) -octahydro-6-azaindole prepared from Example 26 and obtained as a light yellow oil (60 % ).

Example 28

1-fN- (1- S -ethoxycarbonyl-3-phenylpropyl) -S-alanyl] -2-R, S -benzyloxycarbonyl-octahydro-6-azaindole

A solution of 1-ΓΝ- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] -2-R, S -benzyloxycarbonyl-6- (2,2,2-trichloroethoxycarbonyl) -octahydro-6-azaindole (1.48 g, 0.00212 mol) from Example 27 in glacial acetic acid (30 ml) was treated with zinc dust (1.5 g) and the mixture was stirred at room temperature for 16 h. The excess metal was filtered off and the solid washed with methylene chloride (30 ml) and water (30 ml) and the combined filtrates evaporated to dryness. The oily residue became

_OO_ , * C Vr I Γ ÖJ

made basic (5M NaOH) and extracted with methylene chloride (2 × 75 ml), and the extracts were washed with water (50 ml), dried over sodium sulfate and evaporated to give the pure title product as a pale yellow oil (0.97 g, 88 %). received.

Example 29

! -CN- (l-S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] -2-R, S-benzyloxycarbonyl-6- (N-methylcarbamoyl) -octahydro-6-azaindole

A solution of 1-N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] -2-R, S-benzyloxycarbonyl-octahydro-6-azaindole (0.92 g, 0.000176 mol) from Example 28 in methylene chloride (25 ml) was added at 0 C with methyl isocyanate (O.lO g, O.OO175 mol) and stirred for 15 min. The solution was concentrated and the resulting yellow oil was chromatographed over silica gel (10 g) with ethyl acetate and then ethyl acetate / methanol (98: 2) as eluent to give the pure title product as a pale yellow oil (0.80 g, 79 %) ,

Found: C 66. ko H 7- ^ 3 N 10.04% Calculated: C 66.0% H 7-32 N 9-68 % for ^C 32 ^H 42 ^N 4 ^O 6 Separation of the two diastereomers contained in this material was by means of column chromatography possible over silica gel.

7 83

Example 30

1- [N- (1- S -ethoxycarbonyl-1-phenylpropyl) -S-alanyl3-2-R, S-carboxy-6- (N-methylcarbamoyl) octahydro-6-azaindole hydrate

A solution of 1-CN- (1S-ethoxycarbonyl-3-phenylpropyl) S-alanyl 2 -2R, S-benzyloxycarbonyl-6- (N -methylcarbamoyl) -octahydro-6-azaindole (0.776 g, 0.0013 mol) from Example 29 in ethanol (40 ml) and water (10 ml) was hydrogenated at room temperature and 50 psi (3.5 bar) over palladium-charcoal catalyst (100 mg) for 1 h. The catalyst was filtered off and the filtrate was concentrated to a small volume and water was removed by azeotroping with methylene chloride (3 × 20 ml) to give the expected pure product as a colorless solid (0.57 g, 83%). No clear melting point, but the product slowly decomposes in the range of 99-129 C. Found: C 58. ^ 8 H 7. 15 N 10. 58 % Calculated: C 58.53 H 7. ^ 7 N 10.88 % for

° 25 ^Η 36 ^Ν Λ ^XH 2 ° ^{X 0} ^ ^{1 CH} 2 ^C1 2

Example 31

l-tert-butoxycarbonyl-2-ethoxycarbonyl-6-azaindole

At 0 C, a suspension of sodium hydride (80 %, Ο 16 g, 0.0055 mol) in dry N, N-dimethylformamide (5 ml) with a suspension of 2-ethoxycarbonyl-6-azaindole (10 g, 0.0053 mol ) and stirred at room temperature for 1 h. Within this time, evolution of hydrogen ceased and a clear solution was formed. The mixture was cooled to 0 ° C

and with a slogan of '. Di-tert-butyl dicarbonate (1.15 g, 0.0053 mol) was added and the resulting gel was stirred at room temperature for 18 h. The reaction mixture was poured into ice-water (150 ml) and the solution was extracted with ethyl acetate ( 50 ml × k ); the combined organic extracts were washed with brine (3 ^x 50 ml) and dried over sodium sulfate. Evaporation of the solvents in vacuo gave an orange oil which was chromatographed on silica gel (12 g) first with hexane and then with a 70:30 hexane / ethyl acetate mixture as eluent to give the pure title product as a pale yellow oil (l-37 g , 90%) received.

Found: C 62. ko H 6.35 N 9-84 % Calculated: C 62.05 H 6.25 N 9-65 % for C ^ H ^ N ^

Example 32

L-tert-butoxycarbonyl-2-R, S-ethoxycarbonyl-oetahydr0-6-azaindole '"

A solution of 1-tert-butoxycarbonyl-2-ethoxycarbonyl-6-azaindole (lg, 0.0037 mol) from Example 31 in ethanol (50 ml) and hydrochloric acid (2M, 2.8 ml) was added via platinum oxide at 50 psi (3 · 5 bar) and room temperature. The catalyst was filtered off and the solvents were removed in vacuo to form a semi-solid residue which was dissolved in water (50 ml). The solution was adjusted to pH 7x5 with base and extracted with ethyl acetate (3x50 ml). The organic extracts were dried over sodium sulfate and the solvents. removed in vacuo to give the pure title compound as a yellow oil (0.92 g, 90 %) . Found: C 59-90 H 8.91 N 8.62 % Calculated: C 6Ο.38 H 8.78 N 9-39 % for ^c _l5 ^H ₂ 6 ^N 2 ° 4

, , M J33

Example 33

1-tert-Butoxycarbonyl-2-R, S-ethoxycarbonyl-6- (N-methylcarbamoyl) -octahydro-6-aza-indole

A solution of methyl isocyanate (0.16 g, 0.0028 mol) in dry methylene chloride (5 ml) was added dropwise at 0 C to a stirred solution of 1-tert-butoxycarbonyl-2-R, S-ethoxycarbonyl-octahydro-6-azaindole (0.82 g, 0.00275 mol) in dry methylene chloride (10 ml) and the mixture was stirred at this temperature for 1 h .. The solvent was evaporated in vacuo and the residue was purified over silica gel (12 g) with methylene chloride and a mixture of Methylene chloride and methanol 96: 4 as eluent chromatographed · Evaporation of the relevant fractions gave the pure title compound as a colorless foam (0.88 g, 90%) · Found: C 56.89 H 7.89 N 11.78 % Calculated: C 57 · 44 H 8.22 N 11.82% C HN-O

Example 34 .

l-tert-butoxycarbonyl-2-R, S-carboxy-6- (N-methylcarbamoyl) -octahydro-6-azaindole

A solution of 1- tert -butoxycarbonyl-2-R, S -ethoxycarbonyl-6- (N-methylcarbamoyl) -octahydro-6-azaindole (0.4 g, 0.001 mmol) from Example 33 in a mixture of tetrahydrofuran (20 ml Water (10 ml) and methanol (20 ml) were added with 5M sodium hydroxide solution (1 ml, 0.005 mol) and stirred overnight. The solution was evaporated in vacuo and the residue was dissolved in water (50 ml) and washed with ethyl acetate (3 x 20 ml). The aqueous phase was acidified to pH 2 with 2M hydrochloric acid and extracted with ethyl acetate. The extracts were over sodium sulfate

dried and evaporated to give the pure title product as a colorless foam (0.3 g, 8l %) . Found: C 53.78 H 7-90 N 11.24 % Calculated: C 53 · 63 H 7 · 90 N 11.49 % for

C ₁₅ H ₃₁₅ NO ₅ χ 1/2 H ₂ O x 1/3 ethyl acetate

Example 3 5

l-tert-butoxycarbonyl-2-R, S-benzyloxycarbonyl-6- (N-methyl ^l v_ / carbamoyl) -octahydro-6-azaindole

A solution of 1- tert -butoxycarbonyl-2-R, S-carboxy-6- (N-methylcarbamoyl) -octahydro-6-azaindole (Ig, 0.003 mol) from Example 34 in a mixture of methanol (20 mL) and water (2 ml) was added cesium carbonate solution until pH 7-5 was reached. The mixture was concentrated to dryness and dehydrated by azeotropic distillation with toluene (3 x 20 ml) to give a solid which was suspended in N, N-dimethylformamide (20 ml). Benzyl bromide (0.53 gm 0.003 mol) was added and the mixture was stirred at room temperature overnight The mixture was poured into ice-water (300 ml) and extracted with ethyl acetate (3x100 ml) The combined organic phases were washed with brine (3 × 100 ml), dried over sodium sulfate and evaporated to an oil which was chromatographed over silica gel (10 g) with methylene chloride and then with methylene chloride / methanol 98: 2 as eluent to give the pure title compound as a colorless Foam (0.86 g, 69 %) was obtained.

Found: C 62.93 H 7.37 N 9.87 % Calculated: C 63-29 H 7.46 NlO.06 % for CHNO

- 37 - J & 1783

Example 36

2-R, S-benzyloxycarbonyl-6- (N-methylcarbamoyl) -octahydro-6-azaindole hydrochloride

A solution of 1-tert-butoxycarbonyl-2-R, S-benzyloxycarbonyl-6- (N-methylcarbamoyl) -ocahydro-6-azaindole (.85 g, 0.0020 mol) from Example 35 in dry diethyl ether (80 ml). The solvent was evaporated at 0 ° C with anhydrous hydrogen chloride gas for 30 minutes. The solvent was evaporated to give a semi-solid material which upon stirring with diethyl ether gave the pure title compound as a colorless solid (0.8 g, 96 %) . Found: C 55- ^ 1 H 7-21 N 10.02 % Calculated: C 55 · 8θ H 7-64 N 10.28 % for

C ₁₇ H ₂ NO ₃ χ HCl χ H ₂ O χ 1/2 Et ₂ O

Example 37

1- [N- (l-S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] -2-S-benzyl-oxycarbonyl-6- (N-methylcarbamoyl) -octahydro-6-azaindole

A solution of 2-R, S-benzyloxycarbonyl-6- (N -methylcarbamoyl) -octahydro-6-azaindole hydrochloride (20 g, 0.055 mol) in dry methylene chloride (^ 00 mL) was sequentially treated with N-methylmorpholine at 0 ° C (7.5 g, 0.074 mol), N-hydroxybenzotriazole (2.55 g, Ο.Ο188 mol), N- (1-S-ethoxycarbonyl-3-phenylpropyl) -S-alanine (5.26 g, Ο.Ο188 mol) and (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3 x 6ΐ g, Ο.Ο188 mol) and the mixture was stirred at room temperature for 1.5 h. Further amounts of N-methylmorpholine (2.0 g, 0.02 mol), N-hydroxybenzotriazole (2.55 g, Ο.Ο188 mol), N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanine (5 × 26 g, Ο. Ο188 mol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3 x 6ΐ g, Ο.Ο18 mol) were added to the

- 38 - JS3

again cooled to 0 ° C solution after 2 h and this was repeated after 4 h. The solution was then allowed to stand at room temperature for 72 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (500 ml), the ethyl acetate solution was washed successively with 1M hydrochloric acid (3 x 200 ml), 10% sodium carbonate solution (3 x 200 ml) and brine (3 x 200 ml ) and dried over sodium sulfate. The Solvsns was removed in vacuo and the residual oil on silica gel (300 g) with ethyl acetate / methanol 97O as eluent, wherein the Tite _f lprodukt as the separate pure diastereomers as' light yellow oil (9-96 g, 62.6% of theory) was incurred. Found: C 66.08 H 7 · 39 Ν 9-48 % Calculated: C 66.4l H 7-32 N 9-68 % for ^ο ₃₂ ^Η Ζι2 ^Ν 4 ^Ο 6 [α] ^ ⁵ = -54.5 ° (c = 1, methanol)

Example 38

-PN- (1- S -ethoxycarbonyl-3-phenylpropyl) -S-alanyl] -2-S-carboxy-6- (N-methylcarbamoyl) -octahydro-6-azaindip

A solution of 1-fN- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl3S-benzyloxycarbonyl-o- (N-methylcarbamoyl) -octahydro-6-azaindole (9x6 g, O.Ol66 mol). in ethanol (400 ml) and water (100 ml) was hydrogenated over palladium-charcoal catalyst (Ig) for 2 h at 50 psi (3 x 5 bar). The catalyst was filtered off and the filtrate was concentrated in vacuo to a semi-solid material which was triturated with diethyl ether and collected by filtration and dried to give the pure title compound as a colorless solid (7.8 g, 97%).

Found: C 6Ο.56 Η 7 · 5 ^ Ν 11.05 % Calculated: C 60.34 H 7-50 N 11.26 % for

C ₂₅ H ₃₆ N ₄ O ₆ χ 1/2 H ₂ O

Example 39

! -CN- (1- S -carboxy-3-phenylpropyl) -S-alanyl] -2-S-carboxy-6- (N-methylcarbamoyl) -octahydro-6-azaindole

While stirring, a solution of! -CN- (1-S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] -2-S-CaTbOXy-O- (N-methylcarbamoyl) -octahydro-6-azaindole (2.6 g, 0.0055 mol) of Example 38 in tetrahydrofuran (70 ml) and water (k0 ml) were treated with 5M sodium hydroxide solution (6 ml, 0.03 mol) and stirred at room temperature for 72 h. The solvents were evaporated in vacuo and the resulting semi-solid material was dissolved in water (50 ml). The solution was washed with diethyl ether (3 x 50 ml) and the aqueous phase was passed through a weakly acidic ion exchange resin (kO ml of resin bed) to remove excess base. The aqueous eluates were concentrated in vacuo to a semi-solid material, which was triturated with diethyl ether and evaporated to give a dirty-white powder which, after drying to constant weight at 50 ° C., gave the pure title product (2-77 g, 93 %). ) with a melting point of 176-178 C (with decomposition). Found: C 53 · 82 H 6.8l N 10. kk% Calculated: C 53.66 H 6.67 N 10.01 % for

, ^C 23 ^H 3 O ^N 4 ° 6 ^Na 2 ^XH 2 ° ^{X 1/2 Et} 2 °

Example 4P

1- [N- (1- S -ethoxycarbonyl-3-phenylpropyl) -S-alanyl] -2-S-benzyloxycarbonyl-6- (2,2,2-trichloroethoxycarbonyl) octahydro-6-azaindole

With stirring, a solution of 2-R, S-benzyloxycarbonyl-6- (2,2,2-trichloroethoxycarbonyl) -octahydro-o-azaindole hydrochloride etherate (10.58 g, 0.0224 mol) from Example 26 in dry methylene chloride (200 ml) at 0 ° C with

N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanine (6.26 g, 0.0224 mol), N-hydroxybenzotriazole (3.03 g, 0.027 mol) N-methylmorpholine (4.53 g, 0.0448 mol) and 1- (3 Dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (4.29 g, 0.0224 mol) in four equal-sized portions in two-hour intervals. The reaction mixture was allowed to come to room temperature between 0 C portion-wise additions, but it was again cooled to 0 ° C at the time of further additions of portions. The reaction mixture was then allowed to stir at room temperature for 72 hours. After this time TLC showed that part of the amine starting material was still present, and the reaction mixture was cooled to 0 C and treated with additional N- (1-S-ethoxycarbonyl-3-phenylpropyl) -S-alanine (0.9 ² l g, 0.0034 mol), N-hydroxybenzotriazole (0.45 g, 0.0034 mol), N-methylmorpholine (0.3 g, Ο.ΟΟ34 mol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.64 g, 0.003 μmol) and the solution was allowed to stir for a further 4 hours. The methylene chloride was removed in vacuo and the residue was partitioned between ethyl acetate (300 ml) and water (75 ml). The organic phase was washed with water (2 × 75 ml), 1N hydrochloric acid (4 × 75 ml), water (2 × 75 ml), dilute sodium carbonate solution (4 × 75 ml) and brine (3 × 50 ml) dried over sodium sulfate. The solvent was evaporated in vacuo to give a yellow. Oil , which was chromatographed over silica gel (300 g) with hexane / ethyl acetate 90:10 and then hexane / ethyl acetate 70:30 as eluant to give the title substance as the pure separate diastereomer as a pale yellow oil (5 x 9 g, 76 % of the theoretical yield). Found: C 56.21 H 5-83 N 6.03 % Calculated: C 56.86 H 5.78 N 6.03 % for CJ ^ Cl N ₃ O [] ⁵ = -70 ° (c = 0.12, methanol)

_ _ki _IiJ

example k \

1_ [N- (i-S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] -2-S-benzyloxycarbonyloctahydro-6-azaindole

A solution of 1-fN- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl} -2-S-benzyloxycarbonyl-6- (2,2,2-trichloroethoxycarbonyl) -octahydro-6-azaindole (5-8 g , O.OO832 mol) in glacial acetic acid (120 ml) was treated with zinc dust (5 × 8 g, Ο.88 mol) and stirred overnight at room temperature. The residual metal was removed by filtration and the solids were washed well with water / acetic acid (3 '1, 100 ml). The solvents were removed in vacuo, the residue was basified to pH 10 with 1M sodium hydroxide solution and the solution was filtered. The solids were washed well with methylene chloride. The white phase was extracted with methylene chloride (5 × 100 ml) and the combined organic extracts were washed with brine (2 × 50 ml) and dried over sodium sulfate. The solvents were removed in vacuo to give the pure title product as a viscous yellow oil {k.jk g, 100 %) .

example k2

1-fN (1-S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl3-2-S-benzyloxycarbonyl-6-methanesulphonyl-octahydro-6-azaindole

A solution of 1-CN- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alany1] -2-S-benzyloxycarbonyl-octahydro-6-azaindole (1.2 g, 0.0022 mol) from Example C1 in dry methylene chloride (^ O ml) was added at 0 ° C with N-methylmorpholine (Ο 2227 g, 0.0022 mol) and then with methanesulfonyl chloride (Ο 257 Si 0.0022 mol) in dry methylene chloride

(5 mL) and the reaction mixture was stirred at room temperature for 2 h. TLC showed that there was still a trace of starting amine and therefore additional methanesulfonyl chloride (0.026 g, 0.0002 mol) was added and the solution was stirred at 0 C for 30 min. The solvents were removed in vacuo, the residue was dissolved in ethyl acetate (100 ml) and the solution was washed with water (3 × 30 ml), dried over sodium sulfate and concentrated in vacuo to a yellow gum which was purified over silica gel (20 g ) was chromatographed, eluting with diethyl ether / hexane 90:10, alternating to pure diethyl ether, to give the title compound as a colorless gum (1.01 g, 75%). Found: C 61.84 H 6.94 N 6.70% Calculated: C 62.08 H 6.89 N 7.01% for C ₃₁ H ₄ N ₃ O ₇ S

Example 43

1 ~ Ln (i-S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] -2-S-carboxy-6-methanesulphonyl-octahydro-6-azaindole

A solution of 1-CN- (1-S-ethoxycarbonyl-3-phenylpropyl) -S-alany13-2-S-benzyloxycarbonyl-6-methanesulfonyl-octahydr0-6-azaindole (0.94 g, 0.00157 mol) in a mixture of ethanol (40 ml) and water (10 ml) was hydrogenated following the general procedure of example 38 and the title product as a colorless solid (0.722 g, 89%) with a melting point 100-118 ⁰ C obtained _o Found (dec.): C 55 "89 H 7.05 N 8.02% Calculated: C 55.58 H 7.00 N 8.10% for

^C 24 ^H 35 ^N 3 ° 7 ^SX V2 H ₃ O

Example 4 4

T- [N- (1-S-carboxy-3-phenylpropyl) -S-alanyl3-2-S-carboxy-6-methanesulfonyl-octahydro-6-azaindole

1-10 N- (iS-ethoxycarbonyl-3-ph. -Enylpropyl) -S-alanyl] -2-S-carboxy-6-methanesulfonyl-octahydro-6-azaindole from Example 43 was hydrogenated according to the general method of Example 39 and the title product was obtained as a colorless solid (81%) with a melting point of 145 ° -147 ° C (dec), Found: C 53.55 H 6.34 N 8.43% Calculated: C 53.86 H 6.58 N 8.56% for

C ₂₂ H ₃ N ₃ O ₇ S χ 1/2 H ₂ O

Examples 45-54

The following compounds were prepared according to the general procedures of Examples 42-44, starting with 1- [n- {1-S-ethoxycarbonyl-3-rphenylpropyl) -S-alanylj-2-S-benzyloxycarbonyl-octahydro-6. azaindole and reacted this compound with the appropriate acyl or Sulfonylhalogenxden and then hydrogenated and hydrolyzed to give the monoester or diacid products.

CO-CE-NH-CH

Example no. R ⁴ R ¹ Mp. ⁰ C Glass Analysis% (Theoretical values in C H 6.99 7.20 brackets; N 45 CH ₃ NHSO ₂ C ₂ H ₅ Glass (a) Glass 54.79 (54.38 5.73 5.78 9.98 10:14) 46 CH ₃ NHSO ₂ H (B) Glass 45.07 (45.12 7.70 7.68 7.41) 9.57) 47 (CH ₃ O ₂ NCO C ₂ H ₅ Foam (°) 112-128 (Zers.) 61.00 (61.04 6.74 7.36 9.97 10.95) 48 (CH -) ^ NCO H 144-146 (d) 142-146 58.14 (58.52 7.35 7.19 10.96 11.37) 49 C ₂ H ₅ SO ₂ C ₂ H ₅ (C) 56.73 (56.36 7.29 7.89) 50 C ₂ H ₅ SO ₂ H 51 CH ₃ CONHCO C ₂ H ₅ 52 .CH ₃ CONHCO H 7.32 7.11 53 (CH ₃ ) ₂ NSO ₂ / -I TT 55.89 (55.74 6.96 6.97 9.56 10.40) 54 (CH ₂ VSO ₂ H 53.23 (53.16 9.82 10.78)

(a) Semihydrate, 1/4

(b) 2 1/2 H ₂ O

(c) Semihydrate

(d) hydrate

Example 55

1-ΓΝ- (i-s-ethoxycarbony.l-3-cyclohexylpropyl) '- S-alanyl] -2-S-carboxy-6- (N-methylcarbamoyl) -octahydro-e-azaindole hydrochloride

1- [N- (iS-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] 2-S-carboxy-6- (N-methylcarbamoyl) -octahydro-6-azaindole (0.12 g, Ο.ΟΟΟ25 mol) in ethanol ( 30 ml), water (2 ml) and 2M hydrochloric acid (0 _r 12 ml) was hydrogenated over platinum oxide (10 mg) at room temperature and 60 psi (4.2 bar). The catalyst was filtered off, the filtrate was evaporated in vacuo and the residue was triturated with diethyl ether to give the title product as a colorless solid (100%) of melting point 128 ° -130 ° C (dec.)

 Found: C 53.60 H 8.08 N 9.45% Calculated: C 53.80 H 8.38 N 9.91% for

C ₂₅ H ₄₂ N ₄ O ₆ HCl χ 1 1/2 H ₂ O x 0.1 Et ₂ O

Example 56

T [N ^. (i ^ g ^ carboxy ^ S ^ cyclohexylpropyl) -S-alanyl] -2-S-carboxy-6- (N-methylcarbamoyl) -octahydro-6-azaindole

This compound was prepared by hydrolysis of the product of Example 55 following the general method of Example 3-9 and was obtained as an off-white solid (25%). Found: C 55 "52 H 7.77 N 10.96% Calculated: C 54" 96 H 8.43 N 11.15% for

C ₂₃ H ₃₈ N ₄ O ₆ χ 2 H ₂ O

Example 57

1 - [N- (1-S-ethoxycarbonyl-S-cyclohexylpropyl) -S-alanyl "3-2 ~ S -carboxy-6-methanesulfonyl-octahydro-6-azaindole hydrochloride

This compound was prepared by reduction of the product of Example 43 by the general method of Example 55 and obtained as a colorless solid (100%), mp 145-164 C (dec.).

C) Found: C 51.22 H 7.'63 N 6 _O 36% Calculated: C 51.37 H 7.72 N 7 "48% for

C ₂₄ H ₄₁ N ₃ O ₇ S χ HCl χ 1/2 H ₂ O

Example 58

1-CN (1-S-Carboxy-3-cyclohexylpropyl) -S-alanyl3-2-S-carboxy-6-methanesulphonyl-octahydro-6-azaindole

This compound was prepared by hydrolysis of the product of Example 57 following the general method of Example 39 and as a colorless. Solid (92%). Melting point 15O ° -155 ° C (decomp.) Ο Found: C 53.52 H 7.77. N 7.30% Calculated: C 53.20 H 7.71 N 8.46% for

^C 22 ^H 37 ^N 3 ° 7 ^{SX 1/2 H} 2 °

Example 59

1-CN- (i-R 1 S -ethoxycarbonyl-3-phenylpropyl) -N-benzyloxycarbonyl-S-lysyl-RfS-benzyloxycarbonyl-octahydro-S-azaindole

A. 2-R, S-Benzyloxycarbonyl-6- (2,2,2-trichloroethoxycarbonyl) octahydro-α-azaindole hydrochloride (5.0 g) was treated with N-t-butyloxy-

- Al -

carbonyl-N-benzyloxycarbonyl-L-lysine (4:02 g), 1-hydroxybenzotriazole (1 ₀ 58 g), N-methylmorpholine (2:46 g) and 1- (3-dimethylaminopropyl) -S-ethyl-carbodiimide hydrochloride (2.64 g ) was reacted according to the general procedure of Example 40 to give 1- (Nt-butyloxycarbonyl-N-benzyloxycarbonyl) -S-lysyl) -2-R _/ S-benzyloxycarbonyl-octahydro-6-azaindole as a gum (6.04 g, 68.8%). ) received.

B. The product of (A) (4.9 g) was dissolved in 98% formic acid (75 ml) and the solution was stirred at room temperature for 2 1/2 hours. The solution was concentrated in vacuo and the residual formic acid was removed by azeotroping with methylene chloride (2 × 50 ml). The residual oil was taken up in methylene chloride (200 ml) and the solution was washed with aqueous sodium bicarbonate (2 × 50 ml) and Salt solution (2 × 50 ml) and dried over magnesium sulfate. Evaporation of the solvent gave the unprotected derivative as a gum (4.15 g). Rf 0.2 (silica, ethyl acetate / hexane 2: 1).

C. The product from step (B) (4.15g) was dissolved in methylene chloride (60ml) at 0 ° C and a solution of triethylamine (oo68g) in methylene chloride (10ml) was added, followed by a solution of 2-trifluoromethanesulfonyloxy 4-phenylbutyric acid ethyl ester (2.3 g) in methylene chloride (10 ml). The solution was allowed to come to room temperature and stirred at room temperature for 3 days. The reaction mixture was diluted with methylene chloride (150 ml), washed with 1N hydrochloric acid (3 × 40 ml), aqueous sodium bicarbonate (3 × 40 ml) and brine (2 × 40 ml) and dried over magnesium sulfate. The solution was filtered and evaporated to a gum which was chromatographed over silica with a mixture of hexane and ethyl acetate as eluent. The relevant fractions were pooled and added to 1-fN- (1-R, S-ethoxycarbonyl-3-phenylpropyl) -N -benzyloxycarbonyl-S-lysyl] -2-R, S-benzyloxycarbonyl-6- (2,2,2-) trichloroethoxycarbonyl) -octahydro-6-azaindole (3.75 g) as a gum.

D. The product from step (C) (4.6 g) was dissolved in glacial acetic acid (150 mL) and treated with zinc dust (4.6 g) following the procedure of Example 41 to give the title product as a yellowish oil (3 "4 g) , Rf 0.71 (silica, methyl isobutyl ketone, saturated with 50% aqueous acetic acid).

Example 60

1- {N- (i-Rj-S-ethoxycarbonyl-S-phenylpropyl) -S-leucyl] -2-R, S -benzyloxycarbonyl-octahydro-6-azaindole

A. 2-Bromo-4-phenylbutyric acid ethyl ester (9.17g) in acetonitrile (50ml) was added with stirring to a mixture of L-leucine t-butyl ester (6.14g, free base) and potassium carbonate (2 "4g). in acetonitrile (6o ml) and the mixture was refluxed for 4 hours. The solvent was then evaporated in vacuo and the residue was added with water (50 ml) and extracted with diethyl ether (200 ml). The ether extract was washed with water (3 × 80 ml), dried over magnesium sulfate, filtered and evaporated to an oil. Chromatography on silica with hexane as eluent admixed with 1-10% diethyl ether afforded N- (1-R, S-ethoxycarbonyl-3-phenylpropyl) -S-leucine t-butyl ester as an oil (10.53 g ).

B. Dry hydrogen chloride gas was passed with stirring over a period of 12 hours into an ice-cooled solution of the product (10.53 g) from (A) (above) in diethyl ether (400 ml). The solution was evaporated to dryness, removing traces of HCl by azeotroping with methylene chloride (2 × 100 ml) and diethyl ether (2 × 100 ml). The residue was triturated with a mixture of diethyl ether and hexane (200 mL, 1: 1) and the resulting solid was collected by filtration and dried in vacuo to give N- (1-> r ₇ s -ethoxycarbonyl-3-phenylpropyl). S-leucine hydrochloride (8.6 g). _

- 49 - ^ (g / 1

C. The product of step (B) (7.58 g) was followed with 2-R, S-benzyloxy-carbonyl-6- (2,2,2-trichloroethoxy-carbonyl) -octahydro-6-azaindole hydrochloride (10 g) the general procedure of Example 40 to give 1- [N- (1-R, S-ethoxycarbonyl-3-phenylpropyl) -S-leucyl] -2-R, S-benzyloxycarbonyl-6- (2,2,2 -trichloroethoxycarbonyl) -octahydro-6-azaindole (13.8 g) as a mixture of diastereomers, Rf 0.30, 0.36 (silica, ethyl acetate / hexane 1: 2).

D. The product from step (C) (13.1 g) was dissolved in glacial acetic acid (200 ml) and treated with zinc dust (15.0 g) according to the general procedure of Example 41. Chromatography on silica with chloroform to which up to 3% methanol was added as the eluent gave the title product as a mixture of diastereomers (7.24 g) as an oil. Rf 0.62 (silica, chloroform / methanol 8: 2).

Examples 61 -6 4

The following compounds were prepared from the corresponding intermediate compounds of Formula III described in Examples 59 and 60 above by reaction with methanesulfonyl chloride following the general procedure of Example 42 followed by catalytic hydrogenation and hydrolysis following the procedures of Examples 38 and 34 prepared, wherein the monoester or diacid products were formed.

CH ₃ SO ₂

Example no. R ³ V Mp. ⁰ C Analysis ^£ (Theoretical values in CH 7.42 7.58 5 brackets) N (A) j J i 61 - (CH ₂ ) ₄ NH ₂ C ₂ H ₅ 55.30 (55.46 6.97 7.06 9.39 9.58) (B) 62 - (CHj) ₄ NH ₂  H out of focus 144-160 ° 51.98 (52.47 9.10 9.70) (Dec.) 7.33 7.43 (A) 63 -CH ₂ CH (CH ₃ ,; C ₂ H ₅ If 56.83 (56.92 7.08 7.12 7.47 7.38) 64 -CH ₂ CH (CH ₃ ) ₂ H caJ.20 ^o 57.11 (57.34 8.28 8.02)

(a) hydrate

(b) Hydrate, 1/4 CH ₂ Cl ₂ solvated

Example 65

1-CN- (i-RyS-ethoxycarbonyl-3-phenylpropyl) -N-benzyloxycarbonyl-S-yl, syl3-2-R _/ S-benzyloxycarbonyl-6- (N-methylcarbamoyl) -octahydro-6-azaindole

This compound was prepared by the general method of Example 59 (A) - (C) except that 2-R, S-benzyloxycarbonyl-6- (N-methylcarbamoyl) -octahydro-6-azaindole hydrochloride (Example 36) was used in place of 6 - = - (2, 2, 2-trichloroethoxycarbonyl) derivative was used as the starting material in step (A). The product, a mixture of diastereomers, was obtained as gum (4.3 g), Rf 0.84 (silica, methylene chloride / methanol / ammonium hydroxide 90: 10: 1).

783

 Example 66

1- [N- (IR, S-ethoxycarbonyl-3-phenylpropyl) -S-leucyl3-2-R, S-benzyloxycarbonyl-6- (N-methylcarbamoyl) -octahydro-6- azaindole.

This compound was prepared by the general method of Example 60 (C) except that 2-R, S-benzyloxycarbonyl-6- (N-methylcarbamoyl) -octahydro-6-azaindole hydrochloride (Example 36) was used in place of 2. _r 2,2 ^ trichloroethoxycarbonyl) derivative was used. The product / mixture of diastereomers was obtained as gum (0.35 g) »Rf O" 68, 0.61 (silica, methyl isobutyl ketone, saturated with 50% aqueous acetic acid)

Examples 67-70

The following compounds were prepared from the corresponding intermediate compounds of formula II described in Examples 65 and 66 above by catalytic hydrogenation and hydrolysis according to the procedures of Examples 38 and 16 to obtain the monoester and diacid products, respectively.

CH ₃ NHCO

CO-CH-NH-CH- (CH ₂ )

164 7 S3

Example no. R ³ R ¹ Mp. ⁰ C Analysis% (Theoret. · Values C H 8.13 7.71 in N Klariirer ) 67 - (CHJ ₄ NH ₂ C ₂ H ₅ out of focus -'- 120-140 ° 58.83 (59.22 12. 12. ¹³ (a) (Dec,) 7.43 7.39 68 - (CHJ ₄ NH ₂ H '' Il 54.47 (56.97 7.97 7.98 13. 12. 21 , _u \ 62) 69 -CH ₂ CH (CH ₂ ^C 2 ^H 5 Il 63.18 (63.35 7.39 7.34 10 10 .04 .56) 70 -CH ₂ CH (CH ₂ H Il 59.66 (59.57 10 10 .75 .55) ^UJ

(a) solvated with methylene chloride (0.33 mol) and ethanol (0.1 mol)

(b) solvated with methylene chloride (0.33 mol) _t semihydrate

(c) solvated with methylene chloride (0.33 mol)

Example 71

i-CN-iS-ethoxycarbonyl-S-phenylpropyl) -4S-alanyl-2-S- (2-methyl-1-R, S-propionyloxy-1-propyloxycarbonyl) -6-methanesulfonyloxy-octahydro-S-azaindole hydrochloride , Semihydrate

A mixture of 1-CN- (iS-ethoxycarbonyl-3-phenylpropyl) -S-alanyl '] - 2-S-carboxy-6-methanesulfonyl-octahydro-6-azaindole (0.5'g), propionic acid-1 ^ Chlorr2- methyl propyl ester (0.17 g) and 1,8-diazabicyclo5.4.oJundec-7-ene was refluxed in acetonitrile (20 ml) for 45 min. The solvent was in a vacuum

and the residue was chromatographed over silica gel silica (19 g) with ethyl acetate as eluent. The fractions with the desired product were combined and evaporated to give. the ester as a glass (30 mg) / which was converted to its hydrochloride salt using a solution of hydrogen chloride in diethyl ether. Rf 0.82 (silica, ethyl acetate) _β

Found: C 54.95 H 7..61 N 6.11% Calculated: C 54.49 H 7.23 N 6.15% For

C ₃₁ H ₄₇ N ₃ O ₉ S χ HCl χ 0.5 H ₂ O

Claims (9)

claims 1. A process for preparing antihypertensive octa-hydro-6-azaindole dipeptide derivatives having the formula: _R 4 ι " ⁰ V. (X) CO-CH-NH-CH-CO ₂ R ¹
R ³ R ² and pharmaceutically acceptable salts thereof and bioprecursors therefor, wherein: R is H, C 1 -C 6 -alkyl, C 1 -C 4 -alkenyl or aryl- (C 1 -C 4 -alkyl) is R ₂ is C ₁ -C 4 -alkyl, C ₂ -C 6 -alkenyl, C ₁ -C 6 -cycloalkyl or substituted C ₁ -C 6 -alkyl, in which the substituent is halogen, hydroxyl, C ₁ -C 4 -alkoxy, aryl, aryloxy, aryl 2.. Method according to item 1, .d adurch characterized in that the selectively removable protecting group R 'is a C.C. alkyl group. and the said group is removed by hydrolysis with a base « 3 »method according to item 1, characterized in that the selectively removable protective group R is a benzyl group and the said group is removed by catalytic hydrogenation, 4. The method according to any one of items 1 to 3, characterized in that R ^{2 is} 2-phenethyl. 5 "Process according to one of the items 1 to 3 _r characterized in that R ^!» Is ethyl or 4-aminobutyl. 5 6 5 (0--0, -8KOXy), CzCy-cycloalkyl, -NR R, -NHCOR, χ * » -j ο / -NHCO ₂ R, guanidino, C ₁ -C ₄ -alkylthio, arylthio, aryl- (C ₁ -C ₄ -silyl) thio or a heterocyclic group, R is Cj-Cg-alkyl, C ₃ -C-, -cycloalkyl or a substituted C 1 -C ⁶ -alkyl group, in which the substituent -NHCOR ⁵ , -NHCO ₂ R ⁷ , -NR ⁵ R ⁶ , hydroxy, halogen, -CONR ⁵ R ⁶ , Cj-Cy-cycloalkyl, guanidino, -CO ₂ H, -CO ₂ (C ₁ -C ₄ C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkyl-IiO, aryl or a heterocyclic Group is, • SS R ⁴ -COR ⁵ , -CO ₂ R ⁷ , -SO ₂ R ⁷ , -SO ₂ NR ⁵ R ⁶ , -CONR ⁵ R ⁶ ,
-CON (R ^{5 is} JSO ₂ R ⁷ or -CON (R ^{5 is} JCOR ⁷ , wherein R and R are each independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ cycloalkyl, aryl *, a heterocyclic radical or a substituted C ₁ -C ₆ alkyl group, wherein the group is substituted with one or more
a plurality of halogen atoms or a hydroxy, C ₃ -C ₇ -cycloalkyl- -Si- 6. The method according to any one of items 1 to 3, characterized gekennzeic hnet that R ^{4 is} CONR ⁵ R ⁶ or SO ₂ R ⁷ , wherein R, R and R ^{7 are} as defined in point 1 » 7. The method of item 6 _r as characterized by that R ^{4 is} CONHCH ₃ or SO ₂ CH ₃ . 80 Process according to one of the items 1 to 3, characterized in that the 2-azaindole carbon atom and the carbon , f 2 3 Atoms bearing the R and R substituents have an S configuration. 8 9 Aryl, a "hetero-cyclic" or a -NR R group, ο 9
wherein R and R are each independently H, C - C ₁ - alkyl, -CO (C ₄ -C ₄ alkyl) or aryl, or the two groups R and R, when attached to nitrogen, can be taken together to form a pyrrolidinyl ~ / piperidino-morpholino, piperazinyl or N- (C ₁ -C. -alkyl) -piperazinyl group, and R is as R is defined but hydrogen is not included 11 characterized in that the protecting group R is selected from a compound having the formula: - - (ID where is removed R and R are as defined above, R _er d foregoing definition of R / H, but without including corresponding and R is a selectively removable carboxylic acid protecting group and, if desired, the ester group R is removed by hydrolysis to form the compounds of formula (I) wherein R is H and optionally a pharmaceutically acceptable salt of the product is formed , 9 o Method according to one of the items 1 to 3, characterized in that the compound of the formula I prepared is 1- [N- (1-S-ethoxycarbonyl-3-phenylpropyl) -S-alanylJ-2-S-carboxy- 6- (N -methylcarbamoyl) -octahydro-6-azaindole _/ 1-N- (iS-ethoxycarbonyl-S-phenylpropyl-S-alany ^ - ^ - S-caryboxy-67-methanesulfonyl-octahydro-6-azaindole or 1-fN- (i-carboxy-3-phenylpropyl) -S-lysyl] -2-carboxy-6-methanesulfonyl-octahydro-6-azaindole.